Abstract

Background

Hepatocellular carcinoma (HCC) is a common, highly invasive malignant tumor associated
with a high mortality rate. We previously reported that the aberrant expression of
Snail via activation of reactive oxygen species contributes to the invasive property
of HCC, in part by downregulation of E-cadherin through both transcriptional repression
and epigenetic modification of the E-cadherin promoter. Having demonstrated the ability
of Snail to bind and recruit histone deacetylase 1 and DNA methyltransferase 1 in
this context, we set out to look for other interactions that could affect its ability
to promote oncogenic transformation and cancer cell invasion.

Results

Using cells that stably expressed Snail, we characterized Snail protein interactors
by tandem affinity purification and mass spectrometry. Immunoprecipitation and subcellular
colocalization studies were performed to confirm our identification of the Notch1
intracellular domain (NICD) as a novel Snail-binding partner. NICD interaction with
Snail was found to induce ubiquitination and MDM2-dependent degradation of Snail.
Interestingly, NICD inhibited Snail-dependent invasive properties in both HCC cells
and mouse embryonic fibroblasts.

Conclusions

Our study demonstrates that NICD can oppose Snail-dependent HCC cell invasion by binding
and inducing proteolytic degradation of Snail. Although Notch signaling and Snail
are both widely considered tumor-promoting factors, our findings indicate that the
individual oncogenic contribution of Notch1 and Snail in malignant systems should
be interpreted carefully, particularly when they are conjointly expressed.